Bos, J. L. Ras oncogenes in human cancer: a review. Cancer Res.49, 4682–4689 (1989). CASPubMed Google Scholar
Shields, J. M., Pruitt, K., McFall, A., Shaub, A. & Der, C. J. Understanding Ras: 'it ain't over 'til it's over'. Trends Cell Biol.10, 147–154 (2000). ArticleCASPubMed Google Scholar
Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J. & Der, C. J. Increasing complexity of Ras signaling. Oncogene17, 1395–1413 (1998). ArticleCASPubMed Google Scholar
Wittinghofer, A. Signal transduction via Ras. Biol. Chem.379, 933–937 (1998). CASPubMed Google Scholar
Lowy, D. R. & Willumsen, B. M. Function and regulation of ras. Annu. Rev. Biochem.62, 851–891 (1993). ArticleCASPubMed Google Scholar
Johnson, L. et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev.11, 2468–2481 (1997). ArticleCASPubMedPubMed Central Google Scholar
Seabra, M. C. Membrane association and targeting of prenylated Ras-like GTPases. Cell Signal.10, 167–172 (1998). ArticleCASPubMed Google Scholar
Cox, A. D. & Der, C. J. Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim. Biophys. Acta1333, F51–F71 (1997). CASPubMed Google Scholar
Hancock, J. F., Magee, A. I., Childs, J. E. & Marshall, C. J. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell57, 1167–1177 (1989). ArticleCASPubMed Google Scholar
Hancock, J. F., Paterson, H. & Marshall, C. J. A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell63, 133–139 (1990). References 10 and 11 describe the original characterization of the modification of RAS by farnesylation and, in the case of HRAS and NRAS, but not KRAS, palmitoylation. ArticleCASPubMed Google Scholar
Reuther, G. W. & Der, C. J. The Ras branch of small GTPases: Ras family members don't fall far from the tree. Curr. Opin. Cell Biol.12, 157–165 (2000). ArticleCASPubMed Google Scholar
Takai, Y., Sasaki, T. & Matozaki, T. Small GTP-binding proteins. Physiol. Rev.81, 153–208 (2001). ArticleCASPubMed Google Scholar
Cullen, P. J. & Lockyer, P. J. Integration of calcium and Ras signalling. Nature Rev. Mol. Cell Biol.3, 339–348 (2002). ArticleCAS Google Scholar
Daub, H., Weiss, F. U., Wallasch, C. & Ullrich, A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature379, 557–560 (1996). ArticleCASPubMed Google Scholar
Chiu, V. K. et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell Biol.4, 343–350 (2002). ArticleCASPubMed Google Scholar
Ebinu, J. O. et al. RasGRP, a Ras guanyl nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Science280, 1082–1086 (1998). ArticleCASPubMed Google Scholar
Downward, J., Graves, J. D., Warne, P. H., Rayter, S. & Cantrell, D. A. Stimulation of p21ras upon T-cell activation. Nature346, 719–723 (1990). ArticleCASPubMed Google Scholar
Donovan, S., Shannon, K. M. & Bollag, G. GTPase activating proteins: critical regulators of intracellular signaling. Biochim. Biophys. Acta1602, 23–45 (2002). CASPubMed Google Scholar
Leevers, S. J., Paterson, H. F. & Marshall, C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature369, 411–414 (1994). ArticleCASPubMed Google Scholar
Marais, R., Light, Y., Paterson, H. F. & Marshall, C. J. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J.14, 3136–3145 (1995). ArticleCASPubMedPubMed Central Google Scholar
Yordy, J. S. & Muise-Helmericks, R. C. Signal transduction and the Ets family of transcription factors. Oncogene19, 6503–6513 (2000). ArticleCASPubMed Google Scholar
Pruitt, K. & Der, C. J. Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett.171, 1–10 (2001). ArticleCASPubMed Google Scholar
Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature370, 527–532 (1994). ArticleCASPubMed Google Scholar
Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinaseγ. Cell103, 931–943 (2000). This describes the three-dimensional structure of RAS in complex with one of its effectors, PI3K. The size of the interaction interface shows the difficulty that is likely to face the design of inhibitors of protein–protein interaction. ArticleCASPubMed Google Scholar
Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev.13, 2905–2927 (1999). ArticleCASPubMed Google Scholar
Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H. & Downward, J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J.16, 2783–2793 (1997). ArticleCASPubMedPubMed Central Google Scholar
Lambert, J. M. et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature Cell Biol.4, 621–625 (2002). ArticleCASPubMed Google Scholar
Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature417, 867–871 (2002). ArticleCASPubMed Google Scholar
De Ruiter, N. D., Burgering, B. M. & Bos, J. L. Regulation of the Forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451. Mol. Cell. Biol.21, 8225–8235 (2001). ArticleCASPubMedPubMed Central Google Scholar
Weiss, B., Bollag, G. & Shannon, K. Hyperactive Ras as a therapeutic target in neurofibromatosis type 1. Am. J. Med. Genet.89, 14–22 (1999). ArticleCASPubMed Google Scholar
Mendelsohn, J. & Baselga, J. The EGF receptor family as targets for cancer therapy. Oncogene19, 6550–6565 (2000). ArticleCASPubMed Google Scholar
Kuan, C. T., Wikstrand, C. J. & Bigner, D. D. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr. Relat. Cancer8, 83–96 (2001). ArticleCASPubMed Google Scholar
Bellacosa, A. et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer64, 280–285 (1995). ArticleCASPubMed Google Scholar
Simpson, L. & Parsons, R. PTEN: life as a tumor suppressor. Exp. Cell Res.264, 29–41 (2001). ArticleCASPubMed Google Scholar
Sebti, S. M. & Hamilton, A. D. Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies. Oncogene19, 6584–6593 (2000). ArticleCASPubMed Google Scholar
Cox, A. D. & Der, C. J. Farnesyltransferase inhibitors: promises and realities. Curr. Opin. Pharmacol.2, 388–393 (2002). ArticleCASPubMed Google Scholar
Kohl, N. E. et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nature Med.1, 792–797 (1995). The study that launched massive interest in farnesyl-transferase inhibitors as tumour therapeutic drugs aimed at RAS. Unfortunately, the activity turned out to be selective for HRAS, an isoform that is only very rarely activated in human tumours. ArticleCASPubMed Google Scholar
Lobell, R. B. et al. Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Cancer Res.61, 8758–8768 (2001). CASPubMed Google Scholar
Prendergast, G. C. Actin' up: RhoB in cancer and apoptosis. Nature Rev. Cancer1, 162–168 (2001). ArticleCAS Google Scholar
Ohkanda, J., Knowles, D. B., Blaskovich, M. A., Sebti, S. M. & Hamilton, A. D. Inhibitors of protein farnesyltransferase as novel anticancer agents. Curr. Top. Med. Chem.2, 303–323 (2002). ArticleCASPubMed Google Scholar
Singh, S. B. & Lingham, R. B. Current progress on farnesyl protein transferase inhibitors. Curr. Opin. Drug. Discov. Devel.5, 225–244 (2002). CASPubMed Google Scholar
Cortes, J. E. et al. Efficacy of the farnesyl transferase inhibitor, ZARNESTRATM (R115777), in chronic myeloid leukemia and other other hematological malignancies. Blood31, 31 Oct 31 2002 [epub ahead of print]. Google Scholar
Crooke, S. T. Potential roles of antisense technology in cancer chemotherapy. Oncogene19, 6651–6659 (2000). ArticleCASPubMed Google Scholar
Mukhopadhyay, T., Tainsky, M., Cavender, A. C. & Roth, J. A. Specific inhibition of K-ras expression and tumorigenicity of lung cancer cells by antisense RNA. Cancer Res.51, 1744–1748 (1991). CASPubMed Google Scholar
Chen, G., Oh, S., Monia, B. P. & Stacey, D. W. Antisense oligonucleotides demonstrate a dominant role of c-Ki-RAS proteins in regulating the proliferation of diploid human fibroblasts. J. Biol. Chem.271, 28259–28265 (1996). ArticleCASPubMed Google Scholar
Monia, B. P., Johnston, J. F., Geiger, T., Muller, M. & Fabbro, D. Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nature Med.2, 668–675 (1996). ArticleCASPubMed Google Scholar
HŸser, M. et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J.20, 1940–1951 (2001). Article Google Scholar
Coudert, B. et al. Phase II trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLC) lung cancer. A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report. Eur. J. Cancer37, 2194–2198 (2001). ArticleCASPubMed Google Scholar
Sawyers, C. L. Rational therapeutic intervention in cancer: kinases as drug targets. Curr. Opin. Genet. Dev.12, 111–115 (2002). ArticleCASPubMed Google Scholar
Hoshino, R. et al. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene18, 813–822 (1999). ArticleCASPubMed Google Scholar
Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J. & Saltiel, A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl Acad. Sci. USA92, 7686–7689 (1995). ArticleCASPubMedPubMed Central Google Scholar
Favata, M. F. et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem.273, 18623–18632 (1998). ArticleCASPubMed Google Scholar
Sebolt-Leopold, J. S. Development of anticancer drugs targeting the MAP kinase pathway. Oncogene19, 6594–6599 (2000). ArticleCASPubMed Google Scholar
Sebolt-Leopold, J. S. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med.5, 810–816 (1999). ArticleCASPubMed Google Scholar
Lyons, J. F., Wilhelm, S., Hibner, B. & Bollag, G. Discovery of a novel Raf kinase inhibitor. Endocr. Relat. Cancer.8, 219–225 (2001). ArticleCASPubMed Google Scholar
Normanno, N., Bianco, C., De Luca, A. & Salomon, D. S. The role of EGF-related peptides in tumor growth. Front. Biosci.6, D685–D707 (2001). ArticleCASPubMed Google Scholar
Sibilia, M. et al. The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. Cell102, 211–220 (2000). An elegant transgenic mouse study showing that the ability of activated endogenous RAS protein to promote tumour formation is dependent on the activity of EGFR, indicating the importance of autocrine EGF signalling in RAS transformation. ArticleCASPubMed Google Scholar
Fabbro, D., Parkinson, D. & Matter, A. Protein tyrosine kinase inhibitors: new treatment modalities? Curr. Opin. Pharmacol.2, 374–381 (2002). ArticleCASPubMed Google Scholar
Wakeling, A. E. Epidermal growth factor receptor tyrosine kinase inhibitors. Curr. Opin. Pharmacol.2, 382–387 (2002). ArticleCASPubMed Google Scholar
de Bono, J. S. & Rowinsky, E. K. The ErbB receptor family: a therapeutic target for cancer. Trends Mol. Med.8, S19–S26 (2002). ArticleCASPubMed Google Scholar
Herbst, R. S. ZD1839: targeting the epidermal growth factor receptor in cancer therapy. Expert Opin. Investig. Drugs11, 837–849 (2002). ArticleCASPubMed Google Scholar
Hidalgo, M. et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J. Clin. Oncol.19, 3267–3279 (2001). ArticleCASPubMed Google Scholar
Schulze, A., Lehmann, K., Jefferies, H. B., McMahon, M. & Downward, J. Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev.15, 981–994 (2001). ArticleCASPubMedPubMed Central Google Scholar
Herbst, R. S. & Shin, D. M. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer94, 1593–1611 (2002). ArticleCASPubMed Google Scholar
Robert, F. et al. Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J. Clin. Oncol.19, 3234–3243 (2001). ArticleCASPubMed Google Scholar
Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med.344, 783–792 (2001). The results of the Phase III trials with trastuzumab (Herceptin) that showed it to be an effective treatment for metastatic breast cancer with amplification ofERBB2. ArticleCASPubMed Google Scholar
Xie, Y., Li, K. & Hung, M. C. Tyrosine phosphorylation of Shc proteins and formation of Shc/Grb2 complex correlate to the transformation of NIH3T3 cells mediated by the point-mutation activated neu. Oncogene10, 2409–2413 (1995). CASPubMed Google Scholar
Keshamouni, V. G., Mattingly, R. R. & Reddy, K. B. Mechanism of 17-β-estradiol-induced Erk1/2 activation in breast cancer cells: A role for HER2 and PKC-δ. J. Biol. Chem.277, 22558–22565 (2002). ArticleCASPubMed Google Scholar
Hunger, R. E. et al. Successful induction of immune responses against mutant ras in melanoma patients using intradermal injection of peptides and GM-CSF as adjuvant. Exp. Dermatol.10, 161–167 (2001). ArticleCASPubMed Google Scholar
Reuveni, H. et al. Toward a PKB inhibitor: modification of a selective PKA inhibitor by rational design. Biochemistry41, 10304–10314 (2002). ArticleCASPubMed Google Scholar
Bergo, M. O. et al. Absence of CAAX endoprotease Rce 1: effects on cell growth and transformation. Mol. Cell. Biol.22, 171–181 (2002). ArticleCASPubMedPubMed Central Google Scholar
Kloog, Y., Cox, A. D. & Sinensky, M. Concepts in Ras-directed therapy. Exp. Opin. Investig. Drugs8, 2121–2140 (1999). ArticleCAS Google Scholar
Kimoto, M., Sakamoto, K., Shirouzu, M., Mirao, I. & Yokoyama, S. RNA aptamers that specifically bind to the Ras-binding domain of c-Raf-1. FEBS Lett.441, 322–326 (1998). ArticleCASPubMed Google Scholar
Kato-Stankiewicz, J. et al. Inhibitors of Ras/Raf-1 interaction identified by two-hybrid screening revert Ras-dependent transformation phenotypes in human cancer cells. Proc. Natl Acad. Sci. USA99, 14398–14403 (2002). ArticleCASPubMedPubMed Central Google Scholar
Hidalgo, M. & Rowinsky, E. K. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene19, 6680–6686 (2000). ArticleCASPubMed Google Scholar
Neckers, L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol. Med.8, S55–S61 (2002). ArticleCASPubMed Google Scholar
Zucker, S., Cao, J. & Chen, W. T. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene19, 6642–6650 (2000). ArticleCASPubMed Google Scholar
Rosen, L. S. Angiogenesis inhibition in solid tumors. Cancer J.7 (Suppl. 3), S120–S128 (2001). PubMed Google Scholar
Kirn, D., Niculescu-Duvaz, I., Hallden, G. & Springer, C. J. The emerging fields of suicide gene therapy and virotherapy. Trends Mol. Med.8, S68–S73 (2002). ArticleCASPubMed Google Scholar
Biederer, C., Ries, S., Brandts, C. H. & McCormick, F. Replication-selective viruses for cancer therapy. J. Mol. Med.80, 163–175 (2002). ArticleCASPubMed Google Scholar
End, D. W. et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res.61, 131–137 (2001). CASPubMed Google Scholar
Rose, W. C. et al. Preclinical antitumor activity of BMS-214662, a highly apoptotic and novel farnesyltransferase inhibitor. Cancer Res.61, 7507–7517 (2001). References 86 and 87 describe preclinical data on two of the leading farnesyltransferase inhibitors. The significant effects that are seen in these model systems are probably not due to targeting RAS, and it remains unclear whether they can be replicated in the clinic. CASPubMed Google Scholar